Abstract Body: Atherosclerosis (AS) is the underlying cause of coronary artery disease (CAD). GWAS have identified >300 CAD risk alleles, including lipid-handling genes (e.g., Apoe, Ldlr, Scarb1). Under specific time and/or high fat diet (HFD) conditions, genetic inactivation of key lipid-handling genes can elicit CAD in mice. Contrariwise, loss-of-function (LOF) of a non-lipid handling risk allele (eg, Nos3) has rarely been implicated in murine CAD. Here, strong evidence is provided for a CAD phenotype in mice with vascular smooth muscle cell (VSMC) restricted LOF in Leiomodin1 (Lmod1), a SMC-restricted actin nucleator whose global deletion results in a lethal neonatal uro-gastrointestinal syndrome. Conditional LOF of Lmod1 using Myh11-CreER^T2 resulted in 100% lethality within 1-week of the last tamoxifen dose due to catastrophic ceco-colonic enlargement, precluding the phenotyping of VSMCs. However, male and female mice with Itga8-CreER^T2-mediated deletion of Lmod1 (Lmod1^Itga8) survived for months with hypotension and enlargement of coronary, carotid and aortic vessels. Unexpectedly, angiotensin II and a PCSK9/high fat diet (HFD) showed no cardiac hypertrophy or aneurysmal formation in Lmod1^Itga8 mice; however, these mice exhibited diffuse CAD marked by fibrofatty lesions (Type III-V) within a few weeks of the angiotensin II/PCSK9/HFD regimen. Additional studies demonstrated a fully penetrant phenotype of similar fibrofatty lesions in Lmod1^Itga8 mice without angiotensin II administration; Cre controls under the same tamoxifen/PCSK9/HFD regimen failed to show such CAD. ~30% of Lmod1^Itga8 mice died, though none showed evidence of coronary or cerebral infarction. Surprisingly, there was negligible evidence of AS in arterial vessels of the brain, kidney, liver, lung, mesentery, and spleen. Time course studies documented lipid insudation and VSMC and macrophage foam cell formation in coronary arteries as early as eight days post-PCSK9/HFD. Using a novel immunogold electron microscopy lineage tracing assay, 47% of cells in advanced (>4week) plaques were found to arise from coronary artery SMCs. Bulk RNA-seq and spatial transcriptomics showed pathways related to lipid handling and metabolism in VSMCs as well as defective cardiomyocytes in the vicinity of AS coronary vessels. These studies demonstrate a rapidly manifested CAD phenotype – otherwise impossible to ascertain with traditional SMC Cre drivers – in mice lacking Lmod1, a known human CAD risk allele.